Abstract
Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.
| Original language | English |
|---|---|
| Pages (from-to) | 901-918 |
| Number of pages | 18 |
| Journal | Cancers |
| Volume | 5 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Sep 2013 |
Keywords
- Apoptosis
- BCL2-family
- Cell cycle
- DNA replication
- Kinase inhibitor
- Multiple myeloma
Authors (Note for portal: view the doc link for the full list of authors)
- Authors
- Natoni, A. and Coyne, M. R. and Jacobsen, A. and Rainey, M. D. and O'Brien, G. and Healy, S. and Montagnoli, A. and Moll, J. and O'Dwyer, M. and Santocanale, C.
